Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2α in Pheochromocytoma Cells

Pheochromocytomas and paragangliomas (PPGLs) with activated pseudohypoxic pathways are associated with an immature catecholamine phenotype and carry a higher risk for metastasis. For improved understanding of the underlying mechanisms we investigated the impact of hypoxia and pseudohypoxia on catecholamine biosynthesis in pheochromocytoma cells naturally lacking Hif2α (MPC and MTT) or expressing both Hif1α and Hif2α (PC12). Cultivation under extrinsic hypoxia or in spheroid culture (intrinsic hypoxia) increased cellular dopamine and norepinephrine contents in all cell lines. To distinguish further between Hif1α- and Hif2α-driven effects we expressed Hif2α in MTT and MPC-mCherry cells (naturally lacking Hif2α). Presence of Hif2α resulted in similarly increased cellular dopamine and norepinephrine under hypoxia as in the control cells. Furthermore, hypoxia resulted in enhanced phosphorylation of tyrosine hydroxylase (TH). A specific knockdown of Hif1α in PC12 diminished these effects. Pseudohypoxic conditions, simulated by expression of Hif2α under normoxia resulted in increased TH phosphorylation, further stimulated by extrinsic hypoxia. Correlations with PPGL tissue data led us to conclude that catecholamine biosynthesis under hypoxia is mainly mediated through increased phosphorylation of TH, regulated as a short-term response (24-48 h) by HIF1α. Continuous activation of hypoxia-related genes under pseudohypoxia leads to a HIF2α-mediated phosphorylation of TH (permanent status).Funding: This research was funded by the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio205/1 (project number: 314061271-TRR 205), Project No. B12 (N.B. and G.E.), Project No. B10 (S.R., J.P. and M.U.)and Project No. S01 (A.W., C.G. and M.P.) “The Adrenal: Central Relay in Health and Disease“, and by theParadi erence Foundation (N.B., I.P., S.R. and G.E.).S

No More Free Drug Samples?

Susan Chimonas and Jerome Kassirer argue that giving out “free” drug samples is not effective in improving drug access for the indigent, does not promote rational drug use, and raises the cost of care

The Ethics of Implementation: Institutional Remedies and the Lawyer\u27s Role

The issue addressed in this article is whether and to what extent a lawyer has an ethical responsibility to pursue implementation of the remedy in institutional reform litigation. Institutional reform litigation refers to cases in which an individual or class of individuals sues a large organization in order to vindicate constitutional or statutory rights. The types of cases with which this article is concerned are the public law type, such as school desegregation, prisoners\u27 rights and patients\u27 rights cases, although included under the rubric of institutional reform can be, inter alia, antitrust, reapportionment and bankruptcy cases. The implementation stage of institutional reform litigation arises after an individual or class of individuals prevails at the liability stage, or pursuant to a settlement, and a court orders the defendant organization to change in order to vindicate the plaintiffs\u27 rights. At that point, the defendant organization, whether it be a prison, mental hospital or school district, usually has the burden of implementing the order. One conclusion drawn is that the ethical duty of the lawyer must always be consistent with the lawyer\u27s special responsibility for the quality of justice

Fair Practices in Hiring, Case Analyses

Case analyses of fair practices in hiring in academia

What\u27s a Judge to Do? Remedying the Remedy in Institutional Reform Litigation, a Review of \u3ci\u3eDemocracy by Decree: What Happens When Courts Run Government\u3c/i\u3e by Ross Sandler and David Schoenbrod; Yale University Press (2003)

A review of Democracy by Decree: What Happens When Courts Run Government by Ross Sandler and David Schoenbrod; Yale University Press (2003), in which it is questioned whether judges have the legitimacy and the capacity to oversee the remedial phase of institutional reform litigation

Unlabeled Drug Samples and the Learned Intermediary: The Case for Drug Company Liability without Preemption

Discusses unlabeled drug samples and the learned intermediary. Presents the case for drug company liability without preemption

Termination of Desegregation Decrees and the Elusive Meaning of Unitary Status

Discusses the termination of desegregation decrees and the elusive meaning of unitary status, first introducing the topic and then covering Jenkins III and providing an overview of desegregation scholarship including discretion, capacity, and legitima. Also discusses the evolution of equity, including English equity, American equity, and equity and desegregation. Explores the concepts of relevant rights and interests, focusing on Hohfeld, the interest theory of rights, and the application of the rights theory. The conclusion posits that what remains is a complicated and confused desegregation jurisprudence, and that the lines that separate desegregation from integration from diversity, if there ever were such lines, are blurring. A discussion of the theoretical premises underlying desegregation appears to continue to be necessary

Multijurisdictional Practice for a Multijurisdictional Profession

The issue of multijurisdictional practice ( MJP ) concerns whether, and to what extent, lawyers can practice law in states in which they are not licensed. Under current law in Nebraska and almost every other state, it may be a violation of both the ethics rules and state law for a lawyer not licensed in that state to engage in activity that constitutes the practice of law, even on a temporary basis. This is law that is no longer practical or necessary and Nebraska should now consider modifying it

United States v. Steinmetz: The Legal Legacy of the Civil War, Revisited

One of the enduring and yet unresolved issues concerning the Civil War is its legal nature: Was it an insurrection or an international war? During the war and since, the United States courts have repeatedly been called upon to determine the status of property which was under the control of the Confederacy and its agents during the Civil War. In the process of making such determinations, the courts have reopened questions about the war\u27s legal status. United States v. Steinmetz is such a case

Perceptions of Procedural and Distributive Justice in the September 11th Victim Compensation Fund

The September l1th Victim Compensation Fund (the Fund) was created in response to the terrorist attacks of September 11, 2001. Much has been written about the Fund, both pro and con, in both popular media and scholarly literature. Perhaps the most widely used term in referring to the Fund is unprecedented. The Fund is intriguing for many reasons, particularly for its public policy implications and its impact on the claimants themselves. The federal government has never before provided compensation to victims of terrorism through a special master who had virtually unlimited discretion in determining awards. Consequently, this formal allocation of money by a representative of the federal government to its citizens has provided an opportunity to test theories of procedural and distributive justice in a novel context. This article tests these theories by analyzing the results of a study of the Fund\u27s claimants. Part I provides general background, summarizes existing commentary on the Fund, and discusses prior research on social justice that is relevant to the 9/11 claimants\u27 experiences with the Fund. Part II of this article describes the methodology behind the study, in which seventy-one individuals who filed claims with the Fund completed surveys about their experiences with and perceptions of the Fund. Part III discusses the survey results. We found that participants were reasonably satisfied with the procedural aspects of the Fund, such as representatives\u27 impartiality and respectful treatment. Participants were less satisfied, however, with the distributive aspects of the Fund, such as the unequal distribution of compensation and the reduction in compensation if claimants received compensation from other sources (e.g., life insurance). Part IV of this article addresses the implications of the study results for public policy and for theories of social justice